Tourette's Syndrome (TS) is a childhood-onset neuropsychiatric illness characterized by motor and vocal tics. The cerebral cortex-basal ganglia circuitry regulates motor habits and goal-directed behavior. A question still unanswered is whether there are cellular abnormalities in the basal ganglia and cerebral cortex of TS. We have conducted preliminary postmortem brain tissue studies involving four cases of TS and four normal control (NC) subjects using unbiased stereological techniques. A higher number of parvalbumin (PV)-containing neurons was found in a major output nucleus of the basal ganglia, the internal segment of the globus pallidus (GPi), in TS brains as compared to NC subjects. These are inhibitory neurons projecting to the thalamus. By contrast, PV neuron number and density were decreased in the Caudate (Cd), Putamen (Pt) and insular cerebral cortex in the same TS subjects. The PV neurons are born in the embryonic medial ganglionic eminence (MGE) and tangentially migrate to the striatum and cerebral cortex. The imbalance in PV neuron distribution between cortex, striatum and GPi suggests altered migration or survival of inhibitory neurons in severe, persistent TS. In this proposal, we will use the four TS brain specimens already in our collection plus additional TS brains collected by two different sources to investigate the number and distribution of PV as well as other types of inhibitory neurons in the basal ganglia and cerebral cortex of TS individuals. In the first specific aim we will ascertain whether the number and relative proportion of PV, calretinin (CR), calbindin (CB) and cholinergic (Ach) neurons is altered in striatum and globus pallidus of TS brains as compared to matched NC. In the second specific aim we will estimate the number and proportion of three main cortical interneuron subtypes, containing PV, CB or CR, in TS as compared to NC brains. We will analyze motor and premotor regions and the insula, areas that are overactive during tics, as compared to primary visual cortex, an area not activated by tic behavior. We hypothesize that the altered distribution of PV neurons and possibly of other interneurons will be correlated with TS diagnosis. If confirmed, this hypothesis may represent a catalyst for further investigations on the developmental mechanisms of TS and a step forward in devising future treatment for this disabling condition.